The present study was undertaken to determine the efficacy of ketoconazole in comparison to sodium antimony gluconate (SAG) in the treatment of kala-azar. The study was conducted at two centres: All India Institute of Medical Science, New Delhi and Calcutta School of Tropical Medicine, Calcutta. A total of 180 patients with proven kala-azar were recruited. After preliminary investigations, the patients were randomly divided into 2 groups: One group received ketoconazole in a dose of 600 mg/ day in 3 divided doses for 4 weeks while the other group was treated with SAG at a dose of 20 mg/kg/day up to a maximum of 850 mg/day for 4 weeks. The patients were followed up by clinical examination, liver functions, haemogram and the bone marrow/splenic aspiration. Responders were followed up at 3 and 9 months of intervals. Of 90 cases in SAG, 78 (81.7%) got cured initially while under ketoconazole group, only 26 (33.3%) of 78 patients responded initially (p < 0.001). After 3 months of follow up, 75 of 78 SAG-responders (96.2%) and 24 of 26 ketoconazole-responders (92.3%) continued to be in remission. Despite the fact that 2 patients in each group were lost to follow up at 9 months, similar observations were noted with only one relapse in SAG group. The response to SAG was comparable at the two centres. However, the response to ketoconazole was better at Delhi centre as compared to that at Calcutta. There were no significant side effects or hormonal changes in any of the patients in ketoconazole group at Delhi centre. Significantly higher side effects were reported at Calcutta centre in ketoconazole group (P < 0.05). No satisfactory explanation can be given for this difference in response to ketoconazole at two centres. However, it is known that leishmanial parasites of different geographical origin differ in their response to different drugs and this could be one of the reasons for difference observed in response rate to ketoconazole as the study involved different populations of people.